Riga Stradins University
Vilnis Lietuvietis
PROSTATE CANCER
INCIDENCE,
EFFICIENCY OF DIAGNOSTIC METHODS
AMONG THE RISK GROUP OF MEN
Summary
RIGA-2006
THE TOPICALITY OF THE PAPER
Prostate cancer is one of the most increasingly diagnosed tumours in the world. The
incidence indicators rank it among the second most common oncologic diseases
among men in Latvia. After the introduction of screening tests at the beginning of the
90ies a marked increase in the incidence of prostate cancer was observed. Further
findings in molecular biology and epidemiology changed the existing concepts in
etiology and biology of prostate cancer. The new acquired knowledge has changed the
ways how to prevent and treat prostate cancer in the nearest foreseeable future.
The increasing incidence rate of prostate cancer has also dramatically raised interest
about the causes, diagnostic methods and efficient treatment of this disease.
Humankind has long been trying to find ways how to discover the presence of a
malignant tumour in a human body, particularly focusing on detecting cancer as early
as possible. Historically, the identification of tumour markers has been connected with
the ambition of scientists to develop a special test for early diagnostics of cancer. Ever
since 1928 when Asheim and Zondek described horiongonadotropine as a possible
marker in case of an aggressive horioncarcinoma, intensive research has been ongoing
in this field. The 20th century witnessed gradual evolution of a new direction in
medicine - tumour markers, the main aim of which is directly related to a hope of
early diagnostics of a cancer in a human body.
At present prostate-specific antigen (PSA) is one of the most often determined
tumour marker. Over the last fifteen years, PSA has become a distinct "key" to
detecting prostate cancer. Digital rectal examination (DRE), transrectal
ultrasonography (TRUS) and prostate-specific antigen (PSA) are applied as screening
tests in case of prostate cancer. Before suggesting any test for early diagnostics, it is
important to know real positive and false positive test results. None of the abovementioned tests is perfect for detecting a prostate cancer, which determines the
necessity for additional, more specific tests. By improving the specificity of screening
tests, it is possible to differentiate patients who are likely to die of symptomatic
prostate cancer, from the patients who will live with prostate cancer and die from
different causes. At the Third International Prostate Cancer Consultation held by
WHO in Paris, the necessity for further regional prospective research was
acknowledged in order to determine the optimal PSA and % fPSA cut-off levels, as
well as the parameters of other PSA derivatives with an aim to improve PSA test
specificity (Prostate Cancer, 3 rd Int. Consultation, Paris, 2002).
There is an essential difference in the spread and incidence of prostate cancer as to
different geographical regions of the world. According to the data of Latvia Cancer
Registry, there has been a dramatic increase of incidence of prostate cancer in Latvia the number of incidents has doubled in the last ten years. With 766 newly-diagnosed
cases in 2004, prostate cancer ranks the second most common oncological disease
(after lung cancer) among men. In the last years doctors have daily conducted
increasing numbers of PSA biochemical tests and the consequent prostate biopsies to
examine prostate tissues because of suspected malignancy. Although the specific
number of PSA tests and prostate biopsies is not known, it should be pointed out that
these tests incur high costs and may result in possible health disorders of patients
during the examination (biopsy complications). For that reason, it is very essential to
gain more knowledge and to perform an accurate clinical examination of men with
high-risk in prostate cancer. Hopefully, the present paper will contribute to the
solution of this problem.
THE PURPOSE OF THE PAPER
The purpose of the paper is to study incidence of prostate cancer in Latvia and
evaluate the efficiency of diagnostic methods for a risk-group of men with a PSA
level in serum within the range of 4.0 to 20.0 ng/ml, as well as provide practical
recommendations and solutions to the problem.
OBJECTIVES
1. To study the incidence and mortality rate of prostate cancer in Latvia from 1980 to
2004. By analyzing the findings, to determine the age risk group, age-standartised
incidence, as well as trends in incidence rates.
2. To examine the efficiency of digital rectal examination (DRE), transrectal
ultrasonoscopy TRUS), prostate-specific antigen (PSA) and it derivatives when
trying to diagnose prostate cancer among men at risk of PC with serum PSA level
from 4.0 to 20.0 ng/ml.
3. To study the correlation between the results of morphological examination of
prostate tissues and % free PSA level (free/total PSA ratio) among men at risk of
PC with serum PSA level from 4.0 to 20.0 ng/ml.
4. To provide practical recommendations about diagnostic value of methods for
diagnosis of PC for men at risk of PC with serum PSA level from 4.0 to 20.0 ng/ml.
THE SCIENTIFIC NOVELTY
The present paper is the first detailed study of prostate cancer and its spread in
Latvia. The age group at risk, as well as age-standartised incidence and the trends in
mortality rates have been established.
The diagnostic value of digital rectal examination (DRE), transrectal ultrasonoscopy
(TRUS) of prostate, as well as prostate-specific antigen (PSA) and it derivatives have
been evaluated in detecting prostate cancer among men at risk of PC with serum PSA
level from 4.0 to 20.0 ng/ml.
The correlation between the % free PSA (free/total PSA ratio) level, the results of
morphological examination of prostate biopsies and the degree level of malignancy of
prostate cancer has been established among male patients whose serum tPSA ranges
from 4.0 to 20.0 ng/ml.
It has been found that 18% cut-off level of free PSA (free/total PSA ratio) allows us
to specify the indications for prostate biopsy of male patients whose serum tPSA level
ranges from 4.0 to 10.0 ng/ml. It is recommended to apply this PSA % cut-off level
practically as an additional marker to perform the screening test of prostate cancer.
PRACTICAL SIGNIFICANCE OF THE STUDY
1. The study assesses the sensitivity and specificity of diagnostic methods of prostate
cancer, as well as analyses and determines the possibilities of their practical
application.
2. The study establishes the correlation between prostate-specific antigen (PSA) and the
results of morphological examination of prostate tissue, thus enabling us to determine
the indications for prostate biopsy within the range of tPSA from 4.0 to 10.0 ng/ml and
from 10.01 to 20.0 ng/ml.
3. The results of the research prove that fPSA, f/t PSA, cPSA, indicators improve the
specificity of PSA test thus allowing to reduce the indications for prostate biopsy
among male patients whose PSA is within the range of 4.0 to 10.0 ng/ml.
4. As a result of the study, the 18 % cut-of level of % free PSA (free/total PSA ratio) has
been established, which can vary for male patients with different malignancy degree
of prostate cancer and benign prostate hyperplasia (BPH). Therefore, it is
recommended to apply it as an additional marker for prostate cancer screening.
MATERIALS AND METHODS
During the study we analysed the epidemiological indicators of prostate cancer and the
value of diagnostic methods of prostate cancer for man at risk of PC with serum PSA
level from 4.0 to 20.0 ng/ml.
1.Type of Research
1.1. Epidemiology of prostate cancer - a retrospective study. Data from Latvian State
Cancer Registry over the period of 1980-2004 were analysed. In the course of
research we looked into the newly-diagnosed cases, their number, incidence and
mortality rates (distribution of age groups and stages of the disease), age standardized incidence of prostate cancer and mortality rates in Latvia during the years
of 1980.-2004.
1.2 The value of diagnostic methods for a risk group of man with serum PSA level of 4.0
to 20.0 ng/ml - a prospective study. The study comprised men at the age of 50-75
who volunteered for a venous blood test and a further examination of prostate and
who had an increased PSA level within the range of 4.0 to 20.0 ng/ml.
2. Population of the Study
The study enrolled 226 men at the age of 50 to 75. The average age of the group was
65.8 years, the standard deviation being 5.4 years. Graph 1 show the distribution of
patients according to their age. According to Kolmogorovs -Smirnovs the test data
can be viewed as evenly distributed (2= 1.28; p <0.05).
Age
50-54
55-59
60-64
65-69
70-74
75
Observed
frequency
2,2
11,1
27,4
28,8
27,4
3,1
Expected
frequency
2,6
7,0
15,8
22,4
30,4
21,8
Difference
-0,4
4,0
11,7
6,4
-3,0
-18,7
95% CI
Lower
-1,8
0,4
6,1
0,6
-8,7
21,0
Upper
2,6
8,9
18,0
12,8
3,4
-15,2
Table 1. The comparison of the relative frequency (%) of patients with prostate cancer
enrolled in the research and the data from Latvian Cancer Registry from 1999-2004 in
different age groups, (CI - confidence interval)
3. Diagnostic Methods of Prostate
3.1. Digital Rectal Examination
All patients enrolled in the research group underwent a digital rectal examination
(DRE) of prostate. During the examination presumable indications of prostate cancer
were assessed, e.g., asymmetry, palpable nodules, changes in the density of prostate.
If these indications were present, it was defined as "suspected for prostate ca".
Absence of these indications was interpreted as "non suspected for prostate ca".
3.2. Measurement of PSA and free PSA levels
PSA and fPSA were measured in all men enrolled in the study. Blood test sample
was obtained into v. cubitalis. A 2-3 ml blood sample was taken and tested in a
laboratory during the next 24 hours. Until the blood sample was examined it was
stored in a refrigerator at 2-8° C temperature. Serum PSA and free PSA level were
measured by DPC IMMULITE analyzer device which is applied in vitro and measures
prostate-specific antigen (PSA) and free PSA in human blood serum using the
analyzers IMMULITE and IMMULITE 1000 and which has been accepted in Latvia
for performing immunological examination of blood samples. Diagnostic Products
Corporation (DPC) quality system is registered ISO 13485:2003.
3.3. Transrectal Ultrasonoscopy (TRUS) and prostate biopsy methodology.
Transrectal ultrasonoscopy was performed with TOSHIBA or Britel and Kjaer
ultrasonoscopic consoles with a 7,5 Mhz rectal probes. All male patients involved in
the study underwent prostate volume measurement (cm3); the structure of their
prostate tissue was also assessed. It was considered that during ultrasonoscopy the
following prostate cancer indicators could be detected: 1. asymmetry of prostate, 2.
„echo — negative" tissue areas.
The presence of the mentioned indicators was interpreted as a „Ca positive result",
but all the cases when these indicators were absent were defined as a „Ca negative
result".
All the male patients involved in the study underwent systematic prostate biopsies
under US control by applying 18 G diameter disposable needles. The manipulation
was performed with an automatic biopsy pistol. As a result, 6-10 tissue core biopsy
samples about 15-20 mm long were obtained from different areas of prostate (see
picture 1).
Picture 1. A schematic picture of aimed systemic biopsies of prostate
(s - sagittal biopsies, p - peripheral biopsies)
3.4. Microscopic Examination of Prostate Tissue
To examine the prostate biopsy specimen, both routine and immunohystochemical
examination methods were applied. The study comprised examination of 266 clinical
cases. In each case from 6 to 10 tissue samples were examined. Initially, the prepared
specimen were subject to colouring by hemotoxilin - eozin (HE), which allowed to
determine the type of the tumour, to rate its malignancy degree on the Gleason scale,
the character of tumour invasion according to the diagnostic criteria determined by
WHO.
Every bioptate was marked considering prostate zonal anatomy. The examined
prostate tissues were classified in the following categories:
• Benign prostate tissue (LPH, granulomatous, chronic prostatitis)
• Low- grade intraepithelial neoplasia. » Highgrade intraepithelial neoplasia.
• Prostatic carcinoma
3.5. Statistical analysis
The following statistical methods were used in the study.
3.5.1.Cross-tabulation test. The statistical significance was recognized if p-value is
smaller than 0.05.
3.5.2. The independent samples t-test. This analysis was done in the confidence
interval 95%. The statistical significance was recognized if p-value is smaller
than 0.05.
3.5.3.Dispersion analysis (ANOVA)
The statistical significance was recognized if p-value is smaller than 0.05.
3.5.4. The non-parametric tests:
• Cruscal-Walles test was used to estimate the expression of the findings of
routine morphology (described in degrees) in different groups of prostate cancer
• The correlation of single and multiple linear regressions. The statistically
significant combinations further were analyzed with single factor linear
regression. Than with the significant combinations of single factor linear
regression analysis the multiple linear regressions were performed. The
significant combinations in this analysis in were estimated as the final result
(positive or negative). All analysis has been done by Microsoft SPSS 10
software.
PERSONAL CONTRIBUTION OF THE AUTHOR TO THE COMPLETION OF
THE RESEARCH

The author of the paper developed the strategic basis of the study and
managed the research at all stages.

The author performed the retrospective analyses and data registration.

The author consulted patients and conducted prostate examination (DRE,
TRUS, systematic biopsies).

The author conducted the prospective analysis and data registration

The author developed the proceedings of the morphological analysis and
scientific analysis of the results.

The author processed the acquired data and performed the statistical analysis
of the findings.
RESULTS
1. Incidence and mortality rates of prostate cancer in Latvia from 1980 - 2004.
1.1 General incidence and mortality rates of prostate cancer.
In the period from 1980 to 2004, 8087 new cases of prostate cancer were registered in
Latvian State Cancer Register. In 1980 164 newly-diagnosed cases of prostate cancer
have been registered. Ten years later in 1990 the number increased to 217, but in 2004 it
reached the figure of 766, which in terms of incidence placed prostate cancer the second
most common disease among male oncological diseases (Graph 1).
In the year of 1980 the incidence of prostate cancer in Latvia per 100 000 inhabitants
was 14. 1; in 1995 it increased to 24. 5/100 000 and further went up 71. 4 per 100 000
inhabitants in 2004.
The prostate cancer mortality rate in Latvia per 100 000 inhabitants in 1980 was 8. 1, in
1985 the mortality rate increased to 13. 5 /TOO 000, but in 2004 it reached the figure of
27. 4 per 100 000 inhabitants.
Graph 1. Prostate Cancer age standardised incidence and mortality rates in
Latvia during 1980-2004.
When trying to draw a general conclusion we analysed the average annual increase
of the age standardized incidence rates. Graphs 2, 3 and 4 shows a linear regression
line, straight line direction coefficient "b", its equation and determination coefficient.
The average annual increase of incidence of prostate cancer patients from 1980 to
2004 was
1.19/100 000 inhabitants/per year2.
Graph 2. Prostate Cancer age standardised incidence growth rate in
Latvia during 1980-2004.
From 1980 to 1995 there was a gradual but constant increase of incidence, on
average 0. 27/100 000 inhabitants/per year2.
Graph 3. Prostate Cancer age standardised incidence growth rate in
Latvia during 1980-1995.
From 1996 to 2004 there was a dramatic rise in the incidence rates of prostate
cancer, on average 3. 09/100 000 inhabitants/per year.
Graph 4. The prostate cancer age standardised incidence growth rate in
Latvia from 1995-2004.
Parallel to the incidence increase, the figures also show a constant and steady
rise of mortality rates. However, the increase of mortality rates was not as dramatic as
the incidence rise.
1.2. Analysis of prostate cancer incidence rates in different age groups.
Analysing the average age-standardised incidence of prostate cancer among
patients of different age groups in Latvia over the period of 1980 to 2004, the
incidence maximum is observed in the senior age groups. 10. 7 % of patients are
under 60; 80.1% of patients fall into the age group of 60 to 79. The incidence rates
tend to decrease in older age groups (80 and above).
The highest average incidence rate is noted in the age group of 70 to 74 (Graph 5).
Graph 5. Prostate cancer incidence division by age group in Latvia from 1980-2004.
1.3. Analysis of incidence rates of prostate cancer regarding the stage of the tumour
Graph 7 shows the distribution of the newly-diagnosed prostate cancer cases
according to the stage of the tumour. The recorded total incidence rate increase in most
cases is related to the increase of the second and third stage tumours. It has been observed
that in the mid-80 the metastatic forms of prostate cancer tended to decrease slightly, but
the localised forms of prostate cancer (stage 1 and 2) increased. At the beginning of the
90's there was an increase in the number of cases with stage 3 and 4 prostate cancer. In
1980, 18. 3% of patients did not have an accurately diagnosed stage of the tumour; in
2000 there were 13. 4% of such patients, but in 2004 13. 1 % of all newly-diagnosed
cases did not have accurate assessment of the stage of prostate cancer.
After an overall analysis of incidence rate increase at different stages of prostate
tumour from 1980 to 2004, this study observed a general rise of incidence rate at all
prostate cancer stages (Graph 6).
Analysing the general incidence and mortality rates of prostate cancer in Latvia from
1980 to 2004, as well as the age—standartised incidence rates and their relation to different
stages of prostate cancer, we came to the following conclusions:
1 There was a dramatic increase in general incidence rates of prostate cancer in Latvia
from 1980 to 2004, particularly starting with 1995 and onwards (3.09/100 000
inhabitants/per year 2).
2 There was a constant, steady, but slow increase of mortality rates. However, it was
not as dramatic as the incidence rise observed in the last decade.
3 From 1980 to 2004 the increased incidence rates were observed in older age groups
- 10.7 % of patients were under 60. 80,1% of patients were within the age group of
60 to 79.
4 Generally, the incidence rates show increasing incidence at all stages of prostate
cancer.
2. Descriptive results of all parameters analysed in this study.
2.1.Distribution of male patients involved in the study according to tPSA and %free PSA
level (f/tPSA ratio).
The total serum PSA (tPSA) level of all men enrolled in the study ranged from 4.0
ng/ml to 19,60 ng/ml, the average value 8.73 ng/ml, the standard deviation - 3.98 ng/ml.
The free/total PSA ratio (f/tPSA) of all men involved in the study was within the range
of 0.01 to 0.72, the average value 0.184 ng/ml, the standard deviation -0.117 ng/ml.
2.2. Distribution of men involved in the study according to the results of digital rectal
examination (DRE), transrectal ultrasonoscopy (TRUS) findings, prostate volume,
biopsy results and the grading of prostate cancer cells (Gleason scale).
Prostate DRE results of all man enrolled in the study are shown in graph 7. It has been
established, that in 131 (58%) cases there are no indications of a possible
prostate cancer, but in 95 (42%) cases some prostate cancer indicators have been
found. Palpable tissue hardening is interpreted as an indicator of prostate cancer and
was found in 10 (4%) cases.
Graph 7. Prostate DRE results of all male patients involved in the study
Table 2 shows the distribution of male patients involved in the study according to
the prostate cancer indications found as a result of transrectal ultrasonoscopy (TRUS).
It has been established, that in 104 (46%) cases prostate cancer indications have
been found, but there were no such indications in 122 (54%) cases
TRUS
Rate
%
Ca positive
104
46,0
Ca negative
122
54,0
Total
226
100,0
Table 2. The distribution of male patients involved in the study according
to the results of TRUS examination.
Table 3 shows the distribution of male patients involved in the study according to
the results of morphological examination of prostate tissue. We can see that in 143
(63.3%) cases prostate cancer cells were not obtained (Ca negative), but in 83 (3.7%)
cases the examination identified prostate cancer cells (Ca positive). Moreover, in 17
(7.5%) cases prostate cancer cells simultaneously displayed the indications of high
grade prostatic intraepithelial neoplasia (Ca positive+HgPIN).
Biopsy
Ca negative
Ca positive
Total
Biopsy
Ca positive
N
%
66
29,2
83
36,7
Ca negative
N
%
143 63,3
143 63,3
Total
N
143
66
226
%
63,3
29,2
100,0
Table 3. The distribution of male patients involved in the study according
to the results of morphological examination.
There was a separate study of those cases when prostate cancer was diagnosed after
morphological examination of bioptates. We analysed the distribution of prostate
cancer patients according to the tumour grade.
Table 4 shows the distribution of male patients involved in the study according to
the morphologically proved prostate cancer as a result of biopsy, as well as the
distribution of patients as to the prostate cancer grade according to the Gleason scale.
There were 11(13, 6%) cases of well differentiated prostate cancer (Gleason score
of 4 to 5), 45 (55. 6%) cases of moderately differentiated prostate cancer (Gleason
score of 5 to 6) and 25 (30.9%) cases of poorly differentiated prostate cancer (Gleason
score of 7 to 10).
Gleason score
3
4
5
6
7
8
10
Total
Rate
5
7
20
25
22
3
1
83
%
6,2
7,4
24,7
30,9
27,2
2,5
1,2
100,0
Cumulative %
6,2
13,6
38,3
69,1
96,3
98,8
100,0
Table 4. The distribution of PCa patients as to the malignancy level of
prostate cancer according to the Gleason scale.
2.3. Analysis of the correlation between the morphological changes of prostate
gland and diagnostic methods used in detecting prostate cancer.
2.3.1. The connection between the morphology of prostatic tissue and the results of
digital rectal examination (DRE).
To determine the usefulness of DRE and its results in confirming the suspected
prostate cancer, a statistically credible correlation of the results of digital rectal
examination (DRE) of prostate and the biopsy findings was established. Table 5
shows the results DRE.
DRE
Biopsy
Susp. Ca
No susp. Ca
Total
N
%
N
%
N
%
Ca positive
52
54,7
31
23,7
83
36,7
Ca negative
43
45,3
100
76,3
143
63,3
95
100,0
131
100,0
226 100,0
Total
Table 5. The results of DRE in confirming the suspected prostate cancer and the biopsy.
When analysing the obtained data - distribution of patients according to DRE
findings and biopsy results in separate different total PSA interval groups with the
help of HI-Square test, in the total PSA interval of 4,0-10,0 ng/ml results were
obtained, where Ca positive and Ca negative groups displayed a statistically credible
difference (χ2 = 13.8; p = 0.01). Statistically credible was also the difference in the
interval of total PSA level in serum within the range of 10.1 ≥ 20,0 ng/ml (χ2 = 7.3; p
= 0.01) (Table 6).
DRE
Total PSA
4,0-10,0 ng/ml
10,1 ≥ 20,0 ng/ml
Biopsy
Ca positive
Ca negative
Total
N
%
N
%
N
%
Ca positive
32
50,8
24
22,9
56
33,3
Ca negative
31
49,2
81
77,1
112
66,7
Total
63
100,0
105
100,0
168
100,0
Ca positive
20
62,5
7
26,9
27
46,6
Ca negative
12
37,5
19
73,1
31
53,4
Total
32
100,0
26
100,0
58
100,0
Table 6. The results of DRE in confirming the suspected prostate cancer
and the biopsy in different tPSA intervals.
Table 7 shows the sensitivity, specificity, positive predictive value of DRE test in
total PSA groups.
In the total PSA group of 4.0-10.0 ng/ml, the sensitivity of DRE test in detecting
prostate cancer was 50.8%, specificity - 77.1%, positive predictive value 57.1%. In
the total PSA group of 10.01-20.00 ng/ml, the sensitivity of DRE test in detecting
prostate cancer was 62.5%, specificity - 73.1%, positive predictive value 74.1%.
DRE
4,0-10,0 ng/ml
10,1-20,0 ng/ml
Sensitivity
50,8
62,5
Specificity
77,1
73,1
Positive predictive value
57,1
74,1
Negative predictive value
72,3
61,3
Table 7. The sensitivity, specificity, positive predictive value of DRE test in
different tPSA intervals.
Summing up the analysis of obtained correlation results between DRE and prostatic
biopsy, it has been established:
1. DRE test produces a statistically credible difference of sensitivity and specificity
in groups of male patients with Ca positive and Ca negative biopsy results in both of
the total PSA intervals (4.0-10.0 ng/ml and 10.01-20.0 ng/ml).
2. DRE test shows low diagnostic sensitivity of prostate cancer, but a considerably
higher specificity in diagnosing prostate cancer.
3. There is a considerable difference in positive predictive value of DRE test among
patients with different total PSA intervals (4.0-10.0 ng/ml and 10.01— 20.0 ng/ml).
2.3.2. The correlation between morphological analysis of prostatic bioptates and the
results of transrectal ultrasonoscopy (TRUS).
It has been found that when applying TRUS as a possible diagnostic method of
prostate cancer, a statistically credible correlation was established between the
indications of prostate cancer observed during TRUS examination and the biopsy results.
Table 8 shows the results of the study. In the group of patients where prostate cancer was
diagnosed as a result of biopsy tests, TRUS examination identified prostate cancer
indications in 59 (56.7%) cases. In the group of patients where biopsy test did not
diagnose prostate cancer, TRUS test identified prostate cancer indications in 24 (19.7%)
cases.
Biopsy
Ca positive
Ca negative
Total
TRUS
Ca positive
Ca negative
N
N
%
%
59
56,7
24
19,7
45
43,3
98
80,3
104
100,0
122
100,0
Total
N
%
83
36,7
143
63,3
226
100,0
Table 8. The results of TRUS in confirming the suspected prostate cancer and the biopsy.
Statistical analysis of the obtained data - distribution of patients according to
prostate cancer indicators found during TRUS test and biopsy results assessed with
the help of Hi-Square test, show that there is a statistically credible difference in
different groups of patients (χ2 = 33.2; p = 0.01). There is a credible average
correlation between TRUS findings and biopsy results (Spearman rank correlation
coefficient r = 0.40, p = 0.01). Distribution of patients according to TRUS findings
and biopsy results in separate total PSA intervals differed greatly (Table 9).
Total PSA
4,0 - 10,0 ng/ml
10,1-20,0 ng/ml
Biopsija
Ca positive
Ca negative
Total
Ca positive
Ca negative
Total
Ca positive
N
%
38
42,8
34
57,2
72
100,0
21
65,6
11
34,4
32
100,0
TRUS
Ca negative
N
%
18
18,8
78
81,2
96
100,0
6
23,0
20
77,0
26
100,0
Total
N
56
112
168
27
31
58
%
33,3
66,7
100,0
46,6
53,4
100,0
Table 9. The results of TRUS in confirming the suspected prostate cancer
and the biopsy in different tPSA intervals.
Table 10 shows the sensitivity, specificity, positive predictive value of TRUS
test in different total PSA groups.
In the group with total PSA 4. 0-10.0 ng/ml the sensitivity of TRUS test in
detecting prostate cancer was 52.8%, specificity - 81.3% and positive predictive value
was
67. 9%. In the group with total PSA of 10.01-20.00 ng/ml, the sensitivity of
TRUS test in detecting prostate cancer was 65.6%, specificity - 76.9%, positive
predictive value 77.8%.
TRUS
Sensitivity (%)
Specificity (%)
Positive PV1
Negative PV2
4,0-10,0 ng/ml
52,8
81,3
67,9
69,6
10,1-20,0 ng/ml
65,6
76,9
77,8
64,5
Table 10. The sensitivity, specificity, positive predictive value of TRUS test in
different tPSA intervals.
Summing up the analysis of obtained correlation results between TRUS test
findings and prostatic biopsy, it has been established:
1. TRUS examination produces a statistically credible difference of sensitivity
and specificity among groups of male patients with Ca positive and Ca
negative biopsy results within total PSA intervals (4.0-10.0 ng/ml and 10.0120.0 ng/ml).
1
Positive predictive value
2
Negative predictive value
2. TRUS examination shows low diagnostic sensitivity of prostate cancer
(52.8% un 65.6%) among male patients, whose total PSA ranges from 4.0 to
10.0 ng/ml and 10.1 to 20.0 ng/ml, but a considerably higher specificity
(81% and 76,9%) in detecting prostate cancer in both total PSA intervals
(4.0-10.0 ng/ml and 10.01-20.0 ng/ml).
3. There is an actual difference of positive predictive value of TRUS test:
67.9% vs. 77.8% between different total PSA intervals: (4.0-10.0 ng/ml and
10.01-20.0 ng/ml).
2.3.3. The correlation between morphological analysis of prostatic bioptates and
prostate volume established by TRUS.
Table 11 shows distribution of male patients involved in the study according to
prostate volume established by TRUS test and biopsy results. When taking the
average value of prostate volume, it has been established that the average value of
prostate volume is 47.9 ±1.7 cm3. Analysing the distribution of biopsy results
according to the average value of prostate volume, it was stated that prostate cancer
was diagnosed in 71.3% cases with prostate volume < 48.0 cm3, but 28.8% cases were
found among male patients with prostate volume > 48.0 cm3. But in the group of male
patients where prostate cancer was not diagnosed, there were 55.2% cases with a
prostate volume < 48.0 cm3, but in 44.80% cases the prostate volume was > 48.0 cm3.
Table 11. The distribution patients according to prostate volume
established by TRUS test and biopsy results.
Table 12 shows the correlation of possible diagnosis of prostate cancer and the risk
assessment according to prostate volume established by TRUS test. It was found that
for patients with total PSA 4.0-20.0 ng/ml and taking as a criteria the marginal
prostate volume of 48.0 cm3, the likely diagnosis and risk of prostate cancer is 2.01.
Odds ratio (OR)
Count
Volume, ml (< 48 / >48)
Biopsy = Ca positive
Biopsy = Ca negative
N
2,01
1,57
0,78
226
95% CI
Lover
Upper
1,11
3,63
1,05
2,34
0,64
0,96
Table 12. The correlation of possible diagnosis of prostate cancer and the risk
assessment according to prostate volume established by TRUS test.
2.3.4. The correlation between the morphology of prostatic bioptates, total PSA
(tPSA), free PSA (fPSA), complexed PSA (cPSA), free/total PSA (f/tPSA) ratio.
Table 13 shows the corelation of the results of an independent selective t test of
total PSA and total PSA intervals and the results of prostatic biopsies.
PSA
Variance
t
P
MD
SED
95% CI
Lover
4,0-10,0
ng/ml
10,1-20,0
ng/ml
Upper
Total PSA, ng/ml
1,87
0,06
0,52
0,28
-0,03
1,07
Free PSA, ng/ml
1,26
0,21
0,17
0,13
-0,43
0,09
Compl. PSA, ng/ml
2,66
0,01
0,69
0,26
0,18
1,20
Free/total PSA %
2,78
0,01
0,05
0,02
-0,09
-0,01
Compl/total PSA, %
2,32
0,02
4,04
1,74
0,59
7,48
Total PSA, ng/ml
1,72
0,09
1,30
0,75
-0,21
2,81
Free PSA, ng/ml
1,31
0,19
0,66
0,50
-1,66
0,34
Compl. PSA, ng/ml
2,51
0,02
1,96
0,78
0,39
3,52
Free/total PSA %
1,42
0,16
0,05
0,03
-0,11
0,02
Compl/total PSA %
1,82
0,07
5,77
3,17
-0,59
12,12
Table 13. The correlation of possible diagnosis of prostate cancer and the risk
assessment according to prostate volume established by TRUS test.
A statistically credible difference in the average value of tPSA level among
patients with positive and negative prostate biopsy in both total PSA intervals was
not established.
In the total PSA interval of 4.0-10.0 ng/ml a statistically credible difference
of average value was observed in the following PSA derivatives: complexed PSA
(p=0.01), free/total PSA (p= 0.01), complexed/total PSA (p=0.02).
In the total PSA interval of 10.1-20,0 ng/ml a statistically credible difference
of average value was observed in the PSA derivative - complexed PSA (p=0.02).
2.3.5. The correlation between the morphology of prostate bioptate and total
PSA (tPSA) rate.
Table 14 and graph 9 show the descriptive statistics of total serum PSA (tPSA)
level of patients involved in the study according to biopsy results. In the group of
male patients with prostate cancer confirmed by biopsy (Ca positive) the average
value of tPSA is 9.76, the standard deviation is 4.34; in the group of patients with
benign prostatic tissues (Ca negative), the average value of tPSA is 8.17, the
standard deviation being 3.65. When testing the hypothesis about the equivalence
of the average value of total PSA both in Ca positive and Ca negative group of
patients with the help of an independent selective t test, the obtained results show
that the average values do not differ in a statistically credible way (t = 2.941;
p=0.074).
Biopsy
N
M
SD
SEM
Ca positive
83
9,76
4,34
0,48
Ca negative
143
8,17
3,65
0,31
Table 14. The descriptive statistics of total PSA (tPSA) level in the serum
of patients according to biopsy results.
Graph 9 shows the descriptive statistics of total PSA (tPSA) level among male
patients involved in the study according to biopsy results, in different tPSA intervals
(4.0-10.0ng/ml and 10.01-20.0 ng/ml).
Graph 9. The descriptive statistics of total PSA (tPSA)level among male patients
involved in the study according to biopsy results, in different tPSA intervals
(4.0-10.0ng/ml and 10.01-20.0 ng/ml).
A statistically credible difference of the average value of tPSA among patients with
Ca positive and Ca negative prostate biopsy in both total PSA intervals was not
established:
• In the interval of 4.0-10.0 ng/ml, the average value is 7.1 vs. 6.6, (p=0.06),
• In the tPSA interval of 10.01-20.0 ng/ml, the average value is 15.16 vs. 13.86,
(p=0.09).
When analysing the correlation results between the obtained average value of total
PSA (tPSA) and prostate biopsy, it has been established that:
1. In PSA interval of 4.0 to 20.0 ng/ml total PSA value among male patients with
Ca positive and Ca negative biopsy results do not differ in a statistically credible
way.
2. In PSA interval of 4.0 to 20.0 ng/ml, selecting separate total PSA intervals (4.010.0ng/ml and 10.01-20.0 ng/ml), there is no statistically credible difference of
tPSA value in both Ca positive and Ca negative biopsy result groups.
3. In PSA interval of 4.0-10.0 ng/ml prostate cancer after a biopsy test was
detected less frequently - 56 (33.3%) cases out of 168.
4. In PSA interval of 10.01-20.0 ng/ml prostate cancer after a biopsy test was
detected less frequently - 27 (46.6%) out of 58 cases.
2.3.6. The correlation between the morphology of prostate bioptate, free/total
PSA (f/tPSA) ratio and other PSA derivative rates (values).
Table 15 shows the descriptive statistics of free/total PSA (f/tPSA) ratio
among male patients involved in the study according to the biopsy result, in
different tPSA intervals (4.0-10.0 ng/ml and 10.01-20.0 ng/ml)
When testing the hypothesis about the equivalence of the average value of
free/total PSA ratio both in Ca positive and Ca negative group of patients by
determining the test relevance level (p) according to biopsy results and selecting
separate tPSA intervals, we found that in tPSA interval of 4.0-10.0 ng/ml the
average values differ in a statistically credible way (p<0.01), but in tPSA interval
of 10.01-20.0 ng/ml, the average values of f/t PSA ratio do not differ in a
statistically credible way 0=0.08), (Table 15).
PSA
PSA
Ca positive( biopsy)
N
M
SD
Total PSA, ng/ml
56
7,13
Free PSA, ng/ml
56
4,0-10,0 ng/ml Compl. PSA, ng/ml
Free/total PSA %
SE
Ca negative( biopsy)
N
M
SD
SE
1,51
0,20 112
6,6
1,78
0,17
1,16
0,98
0,13 112
1,3
0,70
0,07
56
5,96
1,55
0,21 112
5,2
1,59
0,15
56
0,16
0,12
0,02 112
0,2
0,11
0,01
Compl/total PSA, % 56 83,70 11,78 1,57 112 79,6 10,05 0,95
Total PSA, ng/ml
27 15,16
2,95
0,57
31
13,8
2,78
0,50
Free PSA, ng/ml
27
2,11
1,90
0,37
31
2,7
1,90
0,34
27 13,05
3,16
0,61
31
11,0
2,78
0,50
Free/total PSA %
27
0,11
0,02
31
0,2
0,13
0,02
Compl/total PSA %
27 85,94 11,33 2,18
31
80,1 12,64 2,27
10,1-20,0 ng/ml Compl. PSA, ng/ml
0,14
Table 15. The descriptive statistics of free/total PSA (ftPSA) ratio among male patients
involved in the study according to the biopsy result, selecting separate tPSA intervals
(4.0-10.0 ng/ml and 10.01-20.0 ng/ml)
The hypothesis about the equivalence of the average values of tPSA in both Ca
positive and Ca negative groups, when analysing separately the age of patients,
the prostate volume, total PSA and its derivatives according to the total PSA
interval and biopsy results was tested by non-parameter statistical tests: MannWitney test, Wilcocson test, test relevance level (p). Table 16 shows the results.
Total PSA
Variance
4-10 ng/ml
>10 ng/ml
U
W
Z
P
U
W
Z
P
Total PSA, ng/ml
2537,5
8865,5
-2,01
0,06
315,00
811,00
-1,61
0,11
Free PSA, ng/ml
2430,0
4026,0
-2,38
0,02
276,50
654,50
-2,21
0,03
Compl. PSA, ng/ml
2390,0
8718,0
-2,51
0,01
283,00
779,00
-2,11
0,03
Free/total PSA
1984,5
3580,5
-3,88
0,01
307,00
685,00
-1,74
0,08
Age, year
2712,0
9040,0
-1,43
0,15
319,50
815,50
-1,55
0,12
Volume, ml
2156,0
3696,0
-2,55
0,01
318,50
643,50
-0,96
0,34
Table 16. The equivalence of the average values of tPSA in both Ca positive and Ca negative
groups, analysis separately by the age of patients, the prostate volume, total PSA and its
derivatives according to the total PSA interval and biopsy results (results of non-parameter
statistical tests: Mann-Witney test-U, Wilcocson test—W, test relevance level -p)
Taking into consideration that there is no statistically credible difference in the
distribution of average value of tPSA between prostate cancer patients and male
patients whose biopsy tests did not prove prostate cancer, but their free PSA (fPSA),
bound PSA (cPSA) and free/total PSA (f/tPSA) ratio was different, the mutual
relevance of tPSA, fPSA, cPSA and f/t PSA was analysed determining Ca negative
result in prostate biopsy test. ROC lines of specificity and sensitivity of Ca negative
results were used for analysis (Graph 10).
Graph 10. The mutual relevance of tPSA, fPSA, cPSA and f/t PSA
in determining Ca negative result in prostate biopsy test.
(ROC lines of specificity and sensitivity of Ca negative result).
Assessing test sensitivity and specificity according to Ca negative biopsy result, in
tPSA interval of 4.0-10,0ng/ml it was found that fPSA (the area below the curved line
= 0.619, p<0.05) produces the highest test sensitivity, followed by tPSA (the area below
the curved line 0.595, p<0.05), but the highest test specificity was produced by f/tPSA
ratio (the area below the curved line =0.316, p<0.01).
Taking into consideration that biopsy test detected prostate cancer in tPSA interval of
4,0-10,0 ng/ml was found in 33.3 % of cases, but in tPSA interval of 10.01-20.0 ng/ml it
was found in 46.6% of cases (close to 50 %), to increase the test specificity we
additionally analysed the correlation of different percentage (%) levels of f/tPSA ratio
according to diagnosed cases of prostate cancer.
Table 17 and graphs 11 and 12 show the statistics of percentage ratio of f/tPSA among
male patients involved in the study according to biopsy results in the total PSA interval of
4.0-10.0 ng/ml.
Total PSA threshold
4.0-10 ng/ml
<0,18
free/total PSA threshold
0,18-0,25
0,25-0,35
>0,35
Sensitivity (%)
40
77
84
91
100
Specificity (%)
28
58
25
8
0
Positive PV
34
48
13
21
41
Negative PV
34
80
57
61
64
Table 17. Comparison of free/total PSA using different thresholds for
patients with a total PSA 4.0-10.0 ng/ml
The data distribution in tPSA interval 4.0-10.0 ng/ml represented in Graph 11 shows
that male patients with cut-off level of f/tPSA ratio >18%, the number of cases with Ca
positive biopsy result was 13 versus 65 Ca negative cases, contrary to the data
distribution in fPSA interval 10.01-20.0 ng/ml represented in Graph 12, where we see 6
Ca positive cases versus 10 Ca negative cases.
When applying the 18% cut-off level of f/tPSA according to diagnosis of prostate
cancer, in tPSA interval 4.0-10.0 ng/ml the test displayed higher sensitivity than in total
PSA level (77% and 40% respectively). The test specificity was also considerably
higher, 58% versus 28% respectively. By setting the percentage level of f/tPSA at 25%,
the test sensitivity according to diagnosis of prostate cancer increased to 84%, but
specificity decreased to 25%.
Graph 11. Comparison of patient with and without prostate cancer using
different free/total PSA thresholds (total PSA 4.0-10.0)
Graph 12. Comparison of patient with and without prostate cancer using different
free/total PSA thresholds (total PSA 10.01-20.00)
When analysing the correlation results between prostate biopsy findings and cutoff
level of free/total PSA (f/tPSA) ratio it was established that:
1. In tPSA interval from 4.0 to 20.0 ng/ml, the difference in average values of f/t
PSA ratio in Ca positive and Ca negative group is statistically significant
(t=3.05; p < 0.01).
2. There is statistically significant difference in average values of f/tPSA ratio in Ca
positive and Ca negative group selecting PSA interval 4.0-10.0ng/ml, (p < 0.01).
3. The average values of f/tPSA ratio in Ca positive and Ca negative group in tPSA
interval 10.01-20.0 ng/ml, does not show any statistically significant difference
(p=0.08).
4. By setting the cut-off level of free/total PSA ratio at „18 %”, sensitivity of Ca
positive result adds up to 77%, i.e., it is possible to detect ¾ of cases, specificity
- 58%.
5. In any of tPSA intervals the age of the patients did not display statistically
significant difference according to biopsy results.
6. The measurements of prostate volume produce a statistically significant
difference according to biopsy results in tPSA interval 4.0-10.0 ng/ml
Table 18 and graphs 13 and 14 show the case distribution of prostate cancer detected
in biopsy according to the percentage level of free/total PSA ratio and malignancy level,
tPSA interval 4.0-10.0 ng/ml, and according to malignancy level of prostate cancer.
The case distribution of prostate cancer detected in biopsy according to the
percentage level of free/total PSA ratio and malignancy level, tPSA interval 4.0-10.0
ng/ml shows that with f/t PSA ratio 0.18 there are on average 6 prostate cancer
malignancy Gleason grades, but with a higher free/total PSA ratio, prostate cancer
malignancy Gleason grades diminish statistically significantly (p<0.05).
Graph 13. Comparison of PCa patient with different Gleason score and without prostate
cancer using different free/total PSA thresholds (total PSA 4.0-10.00)
In total PSA interval 4.0-10.0 ng/ml among patients with Ca negative biopsy result and
prostate cancer detected in biopsy there are statistically credible differences between the
average score on Gleason grading scale and different percentage levels of f/t PSA ratio
(dispersion analysis - F = 3.84; p = 0.015). The results of non-parameter Kruskal-Wallice
test (χ2 = 10,7; p = 0,013) show the same correlation. But in total PSA interval 10.0-20.0
ng/ml such correlation was not identified (F = 2.23; p = 0.11; /=6.12; p = 0.106).
According to the dispersion analysis, in total PSA interval 4,0-10,0 ng/ml there are
statistically significant differences between the average values of percentage level of
f/tPSA among patients with Ca negative and Ca positive biopsy result and Ca positive
patients with different malignancy level of prostate cancer (F = 7.11; p = 0.001). Table
18 shows a considerable difference in the average values of percentage level of
f/t PSA ratio among patients with differentiated and poorly-differentiated prostate
cancer in biopsy (differentiated Ca = 0.184, poorly-differentiated Ca = 0.092).
Total PSA
4.0-10.0 ng/ml
Category
Count
Mean
Ca negative
114
0,205
0,107
1.004E-02
39
0,184
0,132
2.113E-02
15
0,092
0,051
1.332E-02
168
0,191
0,114
8.795E-03
Differentiated
Ca
Poorly
differentiated
Ca
Total:
Stand, deviation
St. error
Table 18. The average values of percentage level of f/t PSA ratio among patients with
differentiated and poorly - differentiated prostate cancer in biopsy
Graph 14. The correlation between the percentage level of free/total PSA ratio
and malignancy level of prostate cancer detected by biopsy.
Analysing the correlation between the percentage level of free/total PSA ratio and
malignancy level of prostate cancer detected by biopsy it has been established that:
1. For patients with benign prostatic tissues and patients with prostate cancer of
different malignancy level, considering Gleason grading scores, and whose tPSA
interval is 4.0-10.0 ng/ml, there is a statistical difference in the average values of
cut-off levels of f/t PSA ratio (p<0.05).
2. For patients with benign prostatic tissues found in biopsy and patients with
prostate cancer of different malignancy level, considering Gleason grading
scores, and whose tPSA interval is 10.01-20.0 ng/ml, there is no statistical
difference in the average values of cut-off levels of f/t PSA ratio (p>0.05).
ANALYSIS OF THE RESULTS
Epidemiology of Prostate Cancer in Latvia
The present research paper studies the general incidence and mortality rates of prostate
cancer, the incidence in different age groups, as well as stages of the disease at the
moment of diagnosing prostate cancer among male patients in Latvia over a period of
time from 1980 to 2004.
The analysis of general incidence and mortality rate indicators show a significant
increase of prostate cancer morbidity, on average 1. 19/100 000 inhabitants/ per year. An
extremely dramatic rise of prostate cancer morbidity was observed after 1995 (3. 09/100
000 inhabitants/per year). These incidence rates have gone up rather sharply and can be
compared to the rising incidence of prostate cancer in the countries of Western Europe
and North America in the 80ies of the 20th century (Whittemore, 1994, Harvei,1996):
Sweden (1.18/100 000 iedz./g2 ), the USA (2.11/100 000 iedz./g2). The significant
increase in the incidence rates of prostate cancer is due to the early diagnostic programmes
which were successfully introduced in these countries (Lu-Yao GL, 1994).
During the research it was observed that the incidence rates tend to decrease in
later age groups (80 and above). There is a similar trend in other countries as well; this
is due to the fact that there are many undiagnosed prostate cancer cases among male
patients over 80 (Whittemore, l994, Beawley,2001).
How can the rising incidence rates of prostate cancer are explained: does that
present an increased risk or speak of more advanced diagnostic methods?
Etiology of prostate cancer is still inaccurate. The only established risk factors of
prostate cancer are the aging of the population and maintained androgen levels.
Prostate cancer occurrence in particular families and high concordance among
monozygotic twins proves the importance of hereditary factor on the spread of
prostate cancer. However, none of the mentioned factors can explain the rising
incidence rates of prostate cancer in age-standartised groups. The present study shows that
from 1980 to 2004 in Latvia an increase of incidence rates was observed in older age
groups. 10.7 % of patients are under 60; 80,1% patients fall into the age group of 60 and
above. Having analysed the increasing incidence rates and stages of prostate cancer at the
moment of diagnoses, we observe a tendency of growing incidence rates at all stages of
prostate cancer.
On the one hand, the growing incidence rates of prostate cancer can be related to
an increase average life expectancy of men. On the other hand, it can be related to an
overall improvement of general diagnostics of prostate cancer, which was observed after
1995. At that time new drugs (selective an adrenoreceptor blocker, alpha-5-reductase
inhibitors) came to the market and were administered for a conservative LPH therapy.
Awareness campaigns among doctors and population stimulated interest about more
accurate methods of diagnostics of prostate diseases, including prostate cancer.
There are authors who consider that the increasing incidence rates are also partly
due to the increase of diagnosed prostate cancer cases after the operation of
transurethral resection of the prostate (TURP). We can agree that this factor has
contributed to increasing incidence rates of prostate cancer to a certain degree,
because TURP operations were widely applied in Latvia in the mid and late 90ies of the
20the century which relates to increasing incident rates after 1995. Morphological
examination of operation material shows that in about 10 to 14% of cases previously
unsuspected patients have been diagnosed with prostate cancer accidentally (Rohr,
1987). To a certain degree, the increased incidence rates are also determined by the
fact that the patients for transurethral resection of the prostate (TURP) are more
accurately selected. In other studies, this correlation is linked to a significant rise in
general incidence rates of prostate cancer (Potosky, 1990, Paulson, 1994).
In our opinion, the observed increase in incidence rates of prostate cancer is
undoubtedly due to the fact that in Latvia at the end of the 90ies of the 20th century
generally recognized modern diagnostic methods, like prostate-specific antigen (PSA)
test, transrectal ultrasonography (TRUS) and the subsequent prostate biopsy were
introduced. The availability of these diagnostic methods affected the incidence
because it was possible to diagnose prostate tumours at an early stage. Scientists in
other countries also have come to the same conclusions (Brewster,2000, Evans,2003).
However, these conclusions differ from the results of our study. In our opinion, the
significant increase of incidence rates in Latvia was caused by all previously
mentioned circumstances at the end of the 90ies of the 20th century. This opinion can
be based on several factors. There has been a wide application of TURP operation in
Latvia starting with 1993, awareness campaigns about the new available LHP
medication since 1995, introduction of PSA in everyday urological practice since
1998, as well as advanced diagnostics of prostate cancer (TRUS with a subsequent
biopsy) since 1999. The effect of all of these factors in our opinion has aggregated
and resulted in increased incidence rates.
Talking of incidence rates, there is a question of prostate cancer related mortality.
There has been an ongoing debate among doctors-urologists whether the screening
and the following treatment have not become too aggressive.
Being aware that in some cases prostate cancer is a chronic slowly-progressing
disease and that attending health disorders at times can affect the patient's health and
lifespan more seriously than the stage of the cancer or the degree of cell atypicality
(Barnes, 1969), the question of prostate cancer related mortality became very topical
in our study. During our research we concluded that there has been a constant and
gradual increase of prostate cancer related mortality rates since 1980. The mortality
rate increase has not been that significant in comparison with incidence rates.
However, the age-standartised mortality rates have almost tripled in the last 24 years:
6.9/100 000 inhabitants in 1980, reaching 17.7/100 000 inhabitants in 2004.
Analyzing all this information, it should be pointed out that there was an increase of
incidence rates at all stages of the disease. Likewise, the percentage of the cases when
the stage of the disease was not determined at all (see Graph 6) has not changed. We
can find similar conclusions in studies from Scotland (Brewster, 2000).
This epidemiological data proves that prostate cancer diagnostics in Latvia can still
be advanced. A further application of early diagnostic methods in daily practise not
only in big, centrally located medical centres but also and especially in remote areas
and regions of the country could eventually decrease prostate cancer related mortality
rates. The reports from such countries as the USA and Austria, where a general
screening of the population has been widely introduced, show that with a dynamic
approach of diagnostics and treatment it is possible to decrease prostate cancer related
mortality rates. (Whittemore, 1994; Bartsch, 2001). The reports from the UK conclude
that the increased incidence rates do not affect age-standartised prostate cancer
mortality rates (Brewster, 2000, Evans, 2003).
The conclusion is that the topic of a future study could be the impact of the
introduction of early diagnostics of prostate cancer and modern methods of treatment
on prostate cancer related mortality in Latvia.
Being aware of a significant increase in incidence rates and gradual mortality rate rise
in last decades, question of preventive measures becomes topical. It would be highly
recommended to investigate impact of diet in our country in comparison with Asian and
Oceania countries, where low incidence rates of prostate cancer are present. Role and
importance of hereditary factors should be evaluated.
Analysis of the Diagnostic Methods Applied for Detecting Prostate Cancer.
Digital Rectal Examination.
Traditionally, digital rectal examination (DRE) is considered to be the "golden
standard" in prostate cancer diagnostics. This examination is a standard procedure for
most patients undergoing physical examination. For many years a palpable lump
detected during DRE was considered to be a symptom of prostate cancer. After the
introduction of PSA tests, the relevance of DRE as an isolated diagnostic method of
prostate cancer decreased. (Jacobsen, 1998). The role of this examination as a
screening method of prostate cancer, as well as a way to determine the stage of the
tumour has been diminishing. The insignificant size of tumour at early stages, as well as
its location in such areas of prostate which are difficult to palpate, limit the usefulness
of this method in early diagnostics of prostate cancer. In clinical research, DRE as a
screening method for prostate cancer produces insignificant results: sensitivity 52%,
specificity 81% (Kirby, 1996). The results of our study are relatively even worse, but still
very close to the mentioned: sensitivity 50.8%, specificity -77.1%. DRE often is not
sufficient to assess the spread and the stage of the tumour. The positive correlation
between the findings of DRE and the stage of the tumour is less than 50% of all cases
(Spigelman, 1986).
In our study the distribution of patients according to DRE findings and biopsy results
varied at different PSA intervals. Analysing these findings, we can see that PSA as an
isolated prostate cancer test cannot be approved for patients with a PSA level ≤ 20.0
ng/ml. At the same time, there are a number of reports that mention an even lower total
rate of location of prostate cancer (40 %) during DRE in case of palpable altered texture
of prostate. (Catalona, 1994; Lee, 1988; Ellis,994). The results of our study show that at
the moment DRE is recommended for prostate cancer diagnostics only when combined
with a PSA test. DRE combined with an f/tPSA level < 0.18 is a recommended
diagnostic strategy to suspect prostate cancer in biopsy among patients whose tPSA
ranges from 4.0-10.0 ng/ml. Some reports insist that DRE should be applied as a test to
reduce cancer related mortality, at the same time pointing out that the role of DRE in
prostate cancer diagnostics will be positioned by further research. (Jacobsen, 1998;
Weinmann, 2005).
TRUS, biopsy and prostate volume.
Transrectal ultrasonoscopy (TRUS) is a commonly applied method of prostate
visualization. At the same time ultrasonoscopy is a relatively subjective method and the
results often depend on the experience of the person who performs the test.
The research shows that by applying TRUS as a possible diagnostic method of prostate
cancer, a statistically believable correlation between the indicators of prostate cancer
found during TRUS and biopsy results can be established. In a group of patients the
biopsy test results detected prostate cancer. TRUS examination showed prostate cancer
indicators in 56.7% of all cases. In another group of patients biopsy
did not confirm prostate cancer, while TRUS examination produced 19.7% of cases with
indicators of prostate cancer as a false positive result.
Within the same PSA range of 4.0-10.0 ng/ml, the sensitivity of TRUS
examination detecting prostate cancer was 52.8%, specificity - 81.3%, positive
predictive value 67.9%. With the total PSA range of 10.01-20.00 ng/ml, sensitivity of
TRUS examination detecting prostate cancer was 65.6%, specificity - 76.9%, positive
predictive value 77.8%.
These figures show a low sensitivity level of this method, there is also quite a big
number of false positive cases - 57.2% and 34.4% respectively in both tPSA intervals.
The obtained results do not permit us to recommend TRUS as an independent
prostate cancer diagnostic method. However, the information collected during TRUS
examination about prostate structure and texture asymmetry gives us an idea about the
possible spread of malignant processes. These conclusions relate to the reports on
findings by other researchers who agree that TRUS does not have any special
advantages over DRE according to echogenic texture of tissues. Only 60 % of prostate
cancer can be visualised by TRUS (Smith, 1997). That brings us to the method of
prostate biopsy.
Are the biopsy methods currently used efficient in detecting prostate cancer?
From PSA screening research it is known that about 9 % of asymptomatic male patients
had an increased PSA level in their serum, but only one third of them were diagnosed
with a tumour during a primary biopsy test (Catalona, 1991; Brawer, 1992). The
question is whether 66% of men with an initially negative prostate biopsy have an
increased PSA level because of LHP, because of prostatitis or undetected tumour in
peripheral or transitional area of prostate. Keetch and his co—authors have earlier
proved that cancer can be diagnosed in 19% and 8% of cases only after a second or a
third biopsy test respectively, if cancer was not diagnosed during a primary biopsy. It
should be mentioned that repeated biopsies are performed only in peripheral areas of
prostate. (Keetch, 1995).
There is an ongoing debate about the role of prostate volume as an indicator factor
when deciding in favour of a biopsy method, as well as in the case of repeated biopsy. If
we know that during a sextant biopsy of prostate about 90 mm of prostate tissues (6 x 15
mm samples) are removed for a subsequent microscopic examination, then in case of an
increased prostate the chances of detecting a tumour are significantly reduced (Stamey,
1995; Billebaud, 1992; Vashi, 1998). Since there are many variations of prostate as to
its volume, size and shape, it seems logical that a smaller size prostate can be examined
more intensively, while bigger - less intensively thus influencing the diagnostic result
significantly (Karakiewic, 1996,1998).
Some research groups have suggested new biopsy strategies frequently increasing
the number of biopsies and performing several lateral biopsies. However, we can find
also some controversial data as the actual advantages of these new methods. (Eskew,
1997; Ravery, 1999). Norberg and his co-authors report that applying standard sextant
method of biopsy in 15% of cases cancer is not detected in comparison with the results
produced by applying more extensive biopsy methods and removing 8-10 tissue samples
during one biopsy test. (Norberg, 1997).
The prospective research of Djavan reports about the impact of the volume of
prostate and its transitional area on diagnostics of prostate cancer (Djavan, 2000). When
comparing patients who were diagnosed during the first biopsy with those who were
diagnosed during a repeated biopsy, the latter had bigger total volume of prostate
(32.5+/- 10.6 cm3 vs. 43.1+/-13.0 cm3, p< 0.0001). Analysis of ROC graphs shows that
the total volume of prostate 45 (cm3) provided the best combination of
sensitivity and specificity among patients to whom cancer was diagnosed during the
first biopsy and those who were diagnosed during repeated biopsies. For patients with
total volume of prostate bigger than 45 (cm3), a single sextant biopsy was insufficient
to exclude the diagnosis of cancer. Therefore a repeated biopsy or a more extensive
biopsy procedure should be considered. Thus during our research biopsy method was
enhanced: initially we performed sextant biopsies, later we applied 8-10 bioptate
protocol. Assessing various cancer diagnostic methods as to prostate volume, Uzzo
and his co-authors came to conclusion that 23 % of patients with a volume of prostate
bigger than 50 (cm3) have prostate cancer, but patients with a smaller prostate volume
have cancer in 38% of cases (Uzzo,1995,p<0.01).
In comparison, the findings of our study showed even a greater difference : in
71.3% of cases prostate cancer was diagnosed to patients with prostate volume < 48.0
cm3, but in 28.8 % of cases with prostate volume > 48.0 cm3. The results of our study
relate to the findings of the above-mentioned authors. There is no contradiction also
as to the conclusion that there are more cases of prostate cancer diagnosed among
patients with a smaller prostate than those with a bigger volume of prostate. Increased
tPSA in a smaller prostate is related to the development of cancer while bigger
volume prostate produces a higher level of tPSA by itself.
The 48,0 cm' marginal volume of prostate obtained during the research is
recommended for practical application in daily urological practise to decide about the
necessity of repeated biopsies. Part of the patients were involved in research in 1999
and 2000 when only six sample (or sextant) biopsy strategy was applied which differs
from currently used biopsy strategy of 8—10 samples. Analysing the randomised
reports about 8-10 sample biopsy method versus sextant biopsy technique, no
convincing data has been obtained to prove the relevance of one or the other method
in diagnosing prostate cancer (Naughton, 2000).
Since the results of research point to the limited diagnostic capacity of TRUS
examination, this method nowadays is recommended to measure the volume of
prostate and remove a particular number of bioptates from specific areas of prostate
(systematic biopsy)
Prostate-specific antigen (PSA) and its derivatives.
Analysing the descriptive statistics of total PSA (tPSA) of all male patients
involved in research in comparison with biopsy results within tPSA range of 4.0-20.0
ng/ml, as well as selecting particular tPSA intervals (4.0-10.0ng/ml and 10.01-20.0
ng/ml) it has been found that 168 male patients with tPSA range of 4.0-10.0 ng/ml,
the biopsy tests detected cancer in 33.3% of cases, but in 66.7% of cases prostate
cancer was not diagnosed. 58 male patients with tPSA range of 10.01-20.0 ng/ml
biopsy tests detected prostate cancer in 46.6% of cases, but in 53.4% of patients
prostate cancer was not detected. In the selected tPSA intervals (4.0-10.0 ng/ml and
10.01-20.0 ng/ml), the average value of tPSA between Ca positive and CA negative
patients did not differ significantly which shows that tPSA level alone does not
provide additional diagnostic value to differentiate prostate cancer from other changes
of prostate tissues. However, assessing biopsy results in both groups we can conclude
that in the group of patients with tPSA range of 4.0-10.0 ng/ml there is a bigger
number of negative biopsies (66.7%) in comparison with the other group of patients
with tPSA interval of 10.01-20.0 ng/ml (53.4%). The conclusion is that for patients
with tPSA range of 4.0-10.0 ng/ml additional diagnostic methods should be applied to
improve PSA test specificity. For patients with tPSA interval of 10.01-20.0 ng/ml
prostate biopsy should be indicated in all cases because the probability of prostate
cancer in biopsy test is close to 50 %. Similar strategy is recommended also by other
authors who point out high prostate cancer risk (Reissil, 1996; Van Cangh, 1996). In
daily practise of urologists different PSA derivatives occur (free PSA, bound PSA,
free/total PSA ratio, PSA doubling time, transitional area PSA, etc.) and are applied
to enhance specificity of PSA test. Some studies point to the diagnostic importance of
f/t PSA level ratio for patients with total PSA interval of 4.0-20.0 ng/ml when
detecting patients with prostate cancer. At the same time, they also point out for the
patients with benign prostate hyperplasia (BPH) this ration is higher (Reissil, 1996;
Van Cangh, 1996; Akdas, 1997). In several publications about different populations
the authors mention different f/tPSA marginal level with which f/t PSA tests
demonstrate sufficiently optimal sensitivity and specificity. The results of our study
prove that f/t PSA ration level 0.18 provides optimal sensitivity and specificity of the
test in the common PSA interval of 4.0 to 10.0 ng/ml. The difference between the
patients with prostate cancer and without it is credible, showing sensitivity of 77 %
and specificity of 58 % with a positive and negative predictive result of 48% and 80%
respectively (p<0.05). When increasing f/t PSA ratio level by 0.25, sensitivity of the
test increased to 91 %, but specificity to 25 %. Similar results are reported in several
studies in North America and Europe (Catalona, 1996; Reissil, 1996; Van Cangh,
1996; Akdas, 1997). In order to differentiate between prostate cancer and benign
prostate hyperplasia by applying PSA, several new diagnostic strategies have been
put forward because in many cases in PSA gray area prostate cancer and benign
prostate hyperplasia correlate closely (Lein, 2000).
Although many above-mentioned studies note the importance of clinically applied
methods in prostate cancer diagnostics, like age-related reference ranges, speed of
PSA increase, PSA density and PSA density of transitional area, yet it is recognized
that these indicators do not provide the expected diagnostic effect (Zlotta, 1997;
Carter, 1992; Oesterling, 1993). However, the application of f/tPSA helps to
differentiate prostate cancer from benign prostatic hyperplasia and thus reduces the
number of "unnecessary" biopsies (Tanguay, 2002, Okegawa, 2000).
In the study of Ozdal and his co-authors (Ozdal, 2003) the cohort which represents
the total population of Canada had two indicators (f/tPSA, fPSA/cPSA) and they were
statistically credible and when detecting prostate cancer they provide more
information than tPSA and cPSA alone. Okegawa and his co-authors (Okegawa,
2000) report on similar results. When applying fPSA/cPSA indicator, they observed
the sensitivity and specificity of the method in 93% and 40% of cases respectively.
According to their study, it means that in 9 % of cases it is possible to avoid
unnecessary biopsies when compared to f/tPSA (sensitivity 91% and specificity
31%). Jung and his co-authors (Jung, 2000) report that f/tPSA and cPSA/tPSA are
recommended in order to differentiate prostate cancer from benign prostate
hyperplasia. The application of these derivatives in practise allows us to reduce the
number of "unnecessary" biopsies. f/tPSA - 30 % and cPSA/tPSA 0.26 ng/ml
respectively predicted most accurately positive results of repeated biopsy while bPSA
alone does not provide additional opportunities.
The free/total PSA ratio level established in our research can serve as an additional
indicator to reduce the number of biopsies which do not detect the presence of
prostate cancer because in cases when prostate cancer was detected at f/tPSA ratio
>0.18, the degree of atypicality of cancer cells on Gleason scale was low, i.e., cancer
cells were well differentiated. At later stages of cancer serum PSA level increases.
However, its application possibilities to define cancer stages are very limited. The
results of clinical research prove that there is no direct correlation between serum
PSA level and stage of tumour, although there is a correlation between the
malignancy degree of prostate cancer and f/t PSA ratio indicator. Thus the latter can
be applied as an indicator for predicted malignancy level of prostate cancer cells.
Bangma (Bangma, 1997) reports on similar results.
Summarizing the results of this study, we can conclude that the common
established diagnostic marginal levels of sensitivity and specificity of PSA derivatives
can be applied in daily practise of urologist for diagnosing prostate cancer.
CONCLUSIONS
1. After 1995, there has been a significant increase of prostate cancer incidence, as well
as an invariably stable and slow increase of mortality rate.
2. An increase of prostate cancer incidence can be observed at all stages of the disease;
mostly the highest incidence are registered in the age group of 70 to 75.
3. Male patients whose serum PSA level ranges from 10.01 to 20.0 ng/ml run a high
risk of prostate cancer.
4. Male patients who have a PSA level within the range of 4.0 to 10.0 ng/ml, fPSA,
f/tPSA, cPSA indicators improve the specificity of PSA tests and provide more
accurate indications for a prostate biopsy.
5. When trying to diagnose prostate cancer among men whose serum PSA level ranges
from 4.0 to 20.0 ng/ml, transrectal ultrasonography (TRUS) examination does not
display a greater diagnostic value in comparison with digital rectal examination
(DRE).
6. There is a credible correlation between the volume of prostate determined by TRUS
examination and the results of morphological examination of bioptates. The
correlation between the volume of prostate gland and the age group, on the contrary,
is unlikely.
7. For male patients whose serum PSA level is between 4.0 to l0.0 ng/ml, 18 % volume
of free PSA (free /total PSA ratio) can be indicative of malignancy degree of
suspected prostate cancer.
APPROBATION OF THE PAPER
1. V.Lietuvietis, M.Jakubovskis, S.Gordins, A.Menis, A.Strazdina, MSperga, L.Engele:
Detection of free/total PSA may reduce unnecessary biopsies in men at risk for
prostate cancer - first results, 1-st. Baltic state urologyst Conference, Riga, 1999,
2. V.Lietuvietis, P.Vaganovs, M.Jakubovskis, S.Gordins, A.Menis, A.Strazdina,
M.Sperga, L.Engele: Detection of free/total PSA may reduce unnecessary biopsies
in men at risk for prostate cancer, 18th International Conference on Human Tumor
Markers, Riga, Latvia, 2000,
3. V.Lietuvietis, P.Vaganovs, A.Stengrevics, A.Berzins, J.Gardovskis: Prostate Cancer
in Latvia: A 20-year population study, SIU 26. Congres, Stockholm, 2002,
4. V.Lietuvietis, M.Jakubovskis, A.Strazdiņa, L.Eņģele: Brīvā/saistītā Priekšdziedzera
specifiskā antigēna (PSA) frakciju attiecības nozīme priekšdziedzera vēža agrīnā
diagnostikā, RSU Medicīnas nozares zinātniskās konferences tēzes, Rīsa, 2003 [in
Latvian]
5. V.Lietuvietis, I.Kukulis, E.Vjaters, A.Stengrevics, J.Gardovskis: Prostate Cancer in
Latvia - incidence and mortality last 24 years, Baltijas valstu urologu 4. konference,
Riga, 2005 [in Latvian]
6. V.Lietuvietis, I.Celmina, M.Jakubovskis, S.Gordins, A.Menis, A.Strazdina, U.Teibe,
M.Sperga, L.Engele: Detection of free/total PSA ratio may reduce unnecessary
biopsies in men at risk for prostate cancer: ESMO Genitourinary cancer symposium,
Tartu, Estonia, 2006
7. V.Lietuvietis, I.Kukulis, E.Vjaters, P.Vaganovs, A.Stengrevics, J.Gardovskis, Prostate
Cancer in Latvia: A population study 1980-2004: ESMO Genitourinary cancer
symposium, Tartu, Estonia, 2006
PUBLICATIONS
1. V.Lietuvietis, P.Vaganovs, M.Jakubovskis, S.Gordins, A.Menis, A.Strazdina,
M.Sperga, L.Engele, Detection of free/total PSA may reduce unnecessary biopsies
in men at risk for prostate cancer, Journal of Tumor Marker Oncology, 2001;16(2):
2. V.Lietuvietis, P.Vaganovs, A.Stengrevics, J.Gardovskis, Priekšdziedzera vēzis Latvijā:
Populācijas pētījums 20 gados, Acta Chirurgica Latviensis. 2002;(2):17-21 [in Latvian]
3. V.Lietuvietis, M.Jakubovskis, M.Sperga, A.Strazdiņa, L.Enģele, J.Gardovskis,
Brīvā/Kopējā Priekšdziedzera specifiskā antigēna (b/kPSA) frakciju nozīme
priekšdziedzera vēža diagnostikā, Acta Chirurgica Latviensis. 2003;(3):24-28 [in
Latvian]
4. V.Lietuvietis, S.Doniņa, Priekšdziedzera vēzis - kas notiek šodien? DOCTUS, 2003.g.
okt, 13-17[in Latvian]
5. 5. V.Lietuvietis, M.Jakubovskis, M.Sperga, A.Strazdina, L.Engele, J.Gardovskis, The
Significance of Transrectal Ultrasonography, Digital rectal Examination and
Detection of Prostate - specific Antigen Fraction in Diagnosis of Prostate cancer, Acta
Chirurgica Latviensis. 2004;(4);77-81 [in Latvian!
6. V.Lietuvietis. Priekšdziedzera vēzis - terapeitiska dilemma? DOCTUS, 2005, maijs,
31-32[in Latvian]
7. V.Lietuvietis, I.Kukulis, A.Griņoks, Vai priekšdziedzera vēzis ir neizbēgama
nākotne? DOCTUS, 20005, sept, 38-43 [in Latvian]
8. V.Lietuvietis, Priekšdziedzera vēža skriningdiagnostika, MEDICINE, 2006, feb.,
18-21 [in Latvian]
9. V.Lietuvietis, M.Jakubovskis, M.Sperga, A.Strazdiņa, L. Enģele, J.Gardovskis,
Priekšdziedzera vēzis, diagnostisko metožu nozīme vīriešiem ar seruma PSA 4.0-20.0
ng/ml. RSU rakstu krājums [in Latvian] (confirmed publishing).